We propose a series of interrelated studies in the dog and humans of the interindividual variation in pharmacokinetics of propranolol, a classical example of a drug showing first pass effect. In order to explore in a more definitive fashion the presently accepted theories of the first past phenomena, we have developed precise and specific assays for propranolol, its major metabolites and their conjugates in blood and urine. We propose to use a special dog model which allows repetitive intraportal injections via the hind leg femoral vein to measure hepatic metabolism. The model also allows investigation of gut wall metabolism in the absence of first pass liver metabolism. We therefore plan to measure blood and urine levels of propranolol and its metabolites in order to determine how area under the curve is influenced by dose, route and rate of drug administration. Simultaneous measurements of the blood levels of the metabolites and their excretion rates can be used to estimate the formation rate kinetics of the metabolites and estimation of Michaelis-Menten constants of capacity limited processes. Studies in patients should further our insight into the cause(s) of the elevated first pass bioavailability of propranolol in patients with renal insufficiency and what metabolic pathways are changed in patients with various forms of liver disease. These studies will offer opportunities to gain insights into the fundamental mechanisms of the first pass effect, how it varies between subjects, and into how the pathophysiological liver and kidney diseases influence drug metabolism.